We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.
This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain-Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced by trial therapies intended to diminish the concentration of reactive oxygen species. However, therapies aimed at diminishing reactive nitrogen species have had a more variable outcome, sometimes exacerbating disease. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A 2 . Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosineBrain Pathology 9: 69-92(1999) ࡔ The dot signifies that the compound is a radical, namely a compound possessing one or more unpaired electrons, i.e. electrons that occupy an atomic or molecular orbit by themsleves. This configuration can make the compound reactive. Superoxide and nitric oxide are both radicals, but they are not as reactive as some of their derivatives.
Lesions obtained early in the course of multiple sclerosis (MS) have been studied immunocytochemically, and compared with the early stages of the experimental lesion induced in rats by the intraspinal injection of lipopolysaccharide. Large hemispheric or double hemispheric sections were examined from patients who had died in the course of acute or early relapsing multiple sclerosis. In MS patients exhibiting hypoxia-like lesions [Pattern III; Lucchinetti et al. Ann Neurol (2000) 47: 707-17], focal areas in the white matter showed mild oedema, microglial activation and mild axonal injury in the absence of overt demyelination. In such lesions T-cell infiltration was mild and restricted to the perivascular space. Myeloperoxidase and the inducible form of nitric oxide synthase were expressed primarily by microglia, and the activated form of these cells was associated with extracellular deposition of precipitated fibrin. In addition, these lesions showed up-regulation of proteins involved in tissue preconditioning. When active demyelination started, lesions were associated with massive T-cell infiltration and microglia and macrophages expressed all activation markers studied. Similar tissue alterations were found in rats in the pre-demyelinating stage of lesions induced by the focal injection of bacterial lipopolysaccharide into the spinal white matter. We suggest that the areas of microglial activation represent an early stage of tissue injury, which precedes the formation of hypoxia-like demyelinated plaques. The findings indicate that mechanisms associated with innate immunity may play a role in the formation of hypoxia-like demyelinating lesions in MS.
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